ABSTRACT Quantitative CT Evaluation of Focal Epicardial vs Diffuse Contributions to Coronary Artery Disease PI: Adam M. Alessio The objective of this proposal is to develop clinically viable strategies to quantify the focal epicardial and diffuse contributions to myocardial ischemia with low-dose cardiac CT. There is a pressing need to improve non- invasive testing to identify patients that will benefit from catheterization. Despite significant advances in cardiac diagnostics, over half of coronary catheterizations are performed on patients without obstructive focal coronary artery disease (CAD) incurring substantial expense and resulting in no improvement in patient outcomes. There exist non-invasive options to identify the presence of focal CAD, such as coronary CT angiography, but it is well appreciated that anatomy alone is not sufficient to determine whether a focal stenosis is physiologically significant. Likewise, there exist non-invasive options to assess myocardial perfusion, such as SPECT or PET, but it is also well appreciated that perfusion defects visible on these modalities may have causes other than focal CAD, such as diffuse epicardial CAD or microvascular disease. At best, clinicians aiming to prevent unnecessary catheterizations are left ordering two or more of these types of non-invasive tests and mentally combining them to decide whether their patient has an intervenable, physiologically significant stenosis. This proposal aims to assist clinicians by 1) developing a single non- invasive CT study which assesses both epicardial anatomy and myocardial perfusion and 2) developing quantitative measures which objectively combine stenosis and blood flow information to measure the real functional significance of a stenosis, as well as the quantitative breakdown of how much ischemia is due to focal issues and how much is due to diffuse issues. These methods will be developed and evaluated with patient exams. In particular, this work will leverage existing cardiac CT trial data from a) our previous R01 grant validating cardiac CT perfusion compared to PET and b) our consultants who have a multitude of patients with cardiac CT perfusion exams and matched invasive FFR measurements. In addition, we will conduct a small proof-of-principle study comparing our suite of metrics derived from a single CT exam to invasive FFR and index of microcirculatory resistance (IMR) measures. This project will position cardiac CT as a safe, easy, and widely available tool to understand the real functional significance of focal epicardial stenoses in the presence of diffuse disease and to evaluate diffuse disease in the presence of obstructive focal disease.